The present invention relates to a series of new 1,2-diphenylpyrrole derivatives which have valuable analgesic, anti-inflammatory, anti-pyretic and anti-allergic activities and have the ability to inhibit the production of leukotrienes and to inhibit bone resorption, and which are relatively free from the side effects which generally result from the administration of compounds having these kinds of activities. The invention also provides methods and compositions using these novel compounds as well as processes for their preparation.
Non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used for clinical purposes for the treatment of inflammatory diseases, such as pyrexia, pain and edema. However, the adverse effects of these drugs, such as gastrointestinal disorders and renal disorders, present problems to any patient who takes the drug for an extended period of time as well as to older patients. There are two major metabolic pathways beginning with the arachidonic acids. These are the pathway leading to the production of prostaglandins (PG) and the pathway leading to the production of leukotrienes (LT).
NSAIDs are believed to act by inhibiting the action of PG cyclooxygenase (COX) which is a crucial step in the production of PG from arachidonic acid. It has recently been found that two isozymes, called COX-1 and COX-2, are present in COX.
It has been discovered that COX-1 is normally present in the stomach, the intestines, the kidneys and other tissues and serves to produce PG which functions physiologically, while COX-2 is induced by inflammatory cytokines and endotoxins, such as IL-1, TNF.alpha., and the like, and is expressed specifically at an inflammatory site to produce PG which functions as a mediator of inflammatory reactions. With the discovery of these two isozymes, it was thought that anti-inflammatory agents which specifically inhibit COX-2 without inhibiting COX-1 would be free from the side effects caused by conventional drugs and could be a new type of anti-inflammatory agent.
On the other hand, it is known that IL-1, TNF.alpha., IL-6 and IL-8, the inflammatory cytokines, are produced in monocytes, macrophages and synovial cells as a result of various inflammatory stimulants and influence a number of biological processes, such as the production of PG, the expression of cell adhesion molecules, the production of collagenase-protease, the activation of osteoclasts, pyrexia, the production of acute phase protein, and chemotactic activity of leukocytes.
It is said that these cytokines are associated with the progression of various diseases, such as the chronic inflammatory diseases, including chronic rheumatic arthritis. Thus, drugs which inhibit cytokine actions are useful as a new type of anti-inflammatory agent.
Recently, it has been considered that the prostaglandins, synthesised by the osteoblast cells through induction by COX-2, activate the osteoclast cells and thus induce bone resorption. Accordingly, COX-2 inhibitors are expected to be useful for the treatment and prophylaxis of diseases which are accompanied by or result from bone resorption or destruction, such as osteoporosis, rheumatoid arthritis and osteoarthritis.
Leukotrienes, on the other hand, have been demonstrated to be heavily involved in inflammation, allergy and gastric ulcer formation.
Inhibitors of both LT and PG synthesis are therefore thought to be more desirable drugs for the treatment and prophylaxis of inflammatory diseases.
Amongst the known 1,2-diphenylpyrrole derivatives having analgesic and antiphlogistic actions, a compound represented by the following formula is disclosed in German Patent No. 1938904: ##STR2##
This compound is hereinafter referred to as "Compound A".
However, this compound is not sufficiently effective, and so more effective compounds would be desirable.
We have now discovered a series of new compounds which have the required activity and which do not appear to exhibit the side effects of known compounds. Moreover, the compounds also surprisingly have the ability to inhibit the production of leukotrienes and to inhibit bone resorption, both of which are of therapeutic and prophylactic value.